Acyl-protected hydroxylamines as spin label generators for EPR brain imaging

Alexander T. Yordanov, Ken Ichi Yamada, Murali C. Krishna, Angelo Russo, John Yoo, Sean English, James B. Mitchell, Martin W. Brechbiel

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16 Citations (Scopus)

Abstract

In a search for novel electron paramagnetic resonance (EPR) brain imaging agents, we have designed and synthesized the acyl-protected hydroxylamines 1-acetoxy-4-methoxycarbonyl-2,2,6,6-tetramethylpiperidine (AMCPe), 1-acetoxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (AMCPy), and 1-acetoxy-3-(acetoxymethoxy)carbonyl-2,2,5,5-tetramethylpyrrolidine (DACPy), in which both the ring size and the number of ester functions were varied. In all of them, the nitroxide was first reduced and the resultant hydroxylamine was then protected with an acetyl group. These compounds are lipophilic, which is a major prerequisite for blood-brain barrier penetration. Once in the brain, esterases and oxidants quickly convert these derivatives into ionic, water-soluble radicals and thus EPR detectable species that then reside in the central nervous system for periods of time sufficient for detection and imaging. The biological relevancy of these new compounds in mice has been assessed, and their biodistribution patterns have been compared. The five-membered ring derivative AMCPy emerged as a potent EPR brain imaging agent while the other two derivatives, AMCPe and DACPy, were quite ineffective.

Original languageEnglish
Pages (from-to)2283-2288
Number of pages6
JournalJournal of Medicinal Chemistry
Volume45
Issue number11
DOIs
Publication statusPublished - May 23 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Yordanov, A. T., Yamada, K. I., Krishna, M. C., Russo, A., Yoo, J., English, S., Mitchell, J. B., & Brechbiel, M. W. (2002). Acyl-protected hydroxylamines as spin label generators for EPR brain imaging. Journal of Medicinal Chemistry, 45(11), 2283-2288. https://doi.org/10.1021/jm0105169